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A polyspecific drug/proton antiporter mediates diphenhydramine and clonidine transport at the mouse blood‐retinal barrier
Author(s) -
Chapy Hélène,
André Pascal,
Declèves Xavier,
Scherrmann JeanMichel,
Cisternino Salvatore
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13246
Subject(s) - pharmacology , chemistry , organic cation transport proteins , antiporter , medicine , transporter , biochemistry , membrane , gene
Background and Purpose Transporters at the blood‐retinal barrier ( BRB ), as at the blood–brain barrier ( BBB ), regulate the distribution of compounds into the neural parenchyma. However, the expression of BRB transporters and their quantitative impact in vivo are still poorly understood. Experimental Approach Clonidine and diphenhydramine are substrates of a novel BBB drug/proton‐antiporter. We evaluated their transport at the BRB by in situ carotid perfusion in wild‐type or knocked‐out mice for O ct1‐3 ( S lc22a1‐3). Key Results At pharmacological exposure levels, carrier‐mediated BRB influx was 2 and 12 times greater than the passive diffusion rate for clonidine and diphenhydramine, respectively. Functional identification demonstrated the involvement of a high‐capacity potassium‐ and sodium‐independent proton‐antiporter that shared the features of the previously characterized clonidine, diphenhydramine and cocaine BBB transporter. The functional characterization suggests that SLC transporters O ct1‐3, M ate1 ( S lc47a1) and O ctn1‐2 ( S lc22a4‐5) are not involved. Melanin/retinal toxic drugs like antimalarials (amodiaquine, quinine), quinidine and tricyclic antidepressants (imipramine) acted as inhibitors of this proton‐antiporter. The endogenous indole derivative tryptamine inhibited the transporter, unlike 5‐ HT (serotonin), dopamine or L‐ DOPA . Trans ‐stimulation experiments with [ 3 H ]‐clonidine at the BRB indicated that diphenhydramine, nicotine, oxycodone, naloxone, tramadol, 3,4‐methylenedioxyamphetamine ( MDMA , ecstasy), heroin, methadone and verapamil are common substrates. Conclusions and Implications A proton‐antiporter is physiologically involved in the transport of clonidine and diphenhydramine and is quantitatively more important than their passive diffusion flux at the mouse BRB . The features of this molecularly unidentified transporter highlight its importance in regulating drug delivery at the retina and suggest that it has the capacity to handle several drugs.